This invention relates to dietary supplements. More particularly, this invention relates to compositions and methods for promoting healthy bone structure.
Osteoporosis is a common metabolic bone disease that leads to the gradual loss of mineralized bone from the skeletal mass. This is due in part to an imbalance in the rates of cell-mediated bone deposition and resorption due to the actions of osteoblasts and osteoclasts in the bone matrix. Bone mineral is in a constant state of destruction and repair referred to as “remodeling,” and maintenance of bone density over time is believed to require a precise balance after menopause or during the course of certain disease states. Bone resorption, when exceeding bone formation, can lead to bone fractures resulting from minimal trauma. Unfortunately, there are no symptoms preceding fractures. A common cause of osteoporosis is the decrease in estrogen production following menopause that leads to an increase in bone resorption. Conventional methods to counter bone resorption in women include estrogen therapy and calcium supplementation. Long-term treatment with estrogen has been the only method correlated to significant protection from bone loss in postmenopausal women. See Agnusdei D, Bufalino L. Efficacy of ipriflavone in established osteoporosis and long-term safety. Calcified Tissue International 1997; 61:S23-S27. The isoflavone, ipriflavone, is now successfully used in many countries to treat and prevent osteoporosis.
Ipriflavone (7-isopropoxyisoflavone) was discovered in 1969 by investigators in Budapest while studying plant growth factors. They found that ipriflavone modulates the oxidative phosphorylation mechanisms at the mitochondrial level and subsequently improved cellular oxygen consumption. Later research demonstrated that ipriflavone can increase calcium, phosphorus, and potassium retention in humans, see Agnusdei D, Zacchei F, Bigazzi S, et al. Metabolic and clinical effects of ipriflavone in established postmenopausal osteoporosis, Drugs Exp Clin Res 1989; (XV)2:97-104), and reduce bone turnover rate by inhibiting bone resorption (osteoclasts), see Agnusdei D, Bufalino L. Efficacy of ipriflavone in established osteoporosis and long-term safety. Calcified Tissue International 1997; 61:S23-S27 and Gennari C, Adanii S, Agnusdei D., et al. Effect of chronic treatment with ipriflavone in postmenopausal women with low bone mass, Calcif. Tissue Int. 1997; 61:SI9-S22. Numerous double-blind, placebo-controlled studies have shown a positive effect of ipriflavone in reducing bone mineral loss and increasing bone density in postmenopausal women with osteopenia or established osteoporosis at a dose of 600 mg/day, see Adami S, Bufalino L, Cervetti R, et al., Ipriflavone prevents radial bone loss in postmenopausal women with low bone mass over 2 years, Osteoporosis Int 1997; 7:119-25; Valente M, Bufalino L, Castiglione G N, et al., Effects of 1-year treatment with ipriflavone on bone in postmenopausal women with low bone mass, Calcif. Tissue Int. 1994; 54:377-380; Agnusdei D, Camporeale A, Gonnelli S, et al. Short-term treatment of Paget's disease of bone with ipriflavone, Bone Miner. 1992; 19: (Suppl) S35-S42, Agnusdei D, Zacchei F, Bigazzi S, et al., Metabolic and clinical effects of ipriflavone in established postmenopausal osteoporosis, Drugs Exp Clin Res 1989; (XV)2:97-104; Agnusdei D, Bufalino L., Efficacy of ipriflavone in established osteoporosis and long-term safety, Calcified Tissue International 1997; 61:S23-S27; Kovacs A B, Efficacy of ipriflavone in the prevention and treatment of postmenopausal osteoporosis, Agents Actions 1994; 41:86-7; Passeri, M, Biondi M, Costi D, et al., Effect of ipriflavone on bone mass in elderly osteoporotic women, Bone Miner. 1992: 19: (Suppl) S57-S62.
In these studies, all patients received an oral calcium supplement of 1 g/day in addition to ipriflavone or placebo. One of the researchers, Dr. Donato Agnusdei, stated that “long-term treatment with ipriflavone may be considered safe, and may increase bone density and possibly prevent fractures in elderly patients with established osteoporosis” Agnusdei D, Bufalino L., Efficacy of ipriflavone in established osteoporosis and long-term safety, Calcified Tissue International 1997; 61:S23-S27. Another study evaluating the effects of ipriflavone combined with vitamin D showed that the combined therapy was more effective in reducing bone loss than either therapy alone or control. Ushiroyama T, Okamura S, Ikeda, A, et al., Efficacy of ipriflavone and 1-alpha vitamin D therapy for the cessation of vertebral bone loss, Int J Gynecol Obstet 1995; 48:283-8. A double-blind placebo controlled study of 28 osteoporotic elderly women (having at least one vertebral fracture) taking 600 mg ipriflavone/day along with 1 gram calcium showed a 6% increase (P<0.05) in BMD at the distal radius (DPA). See Passeri, M, Biondi M, Costi D, et al., Effect of ipriflavone on bone mass in elderly osteoporotic women, Bone Miner. 1992: 19: (Suppl) S57-S62. Urinary hydroxyproline/creatinine (HOP/Cr) and serum osteocalcin (BGP) were also reduced in the ipriflavone treated group. Compliance with the oral administration of ipriflavone was good.
All clinical trials confirm a very good tolerance of ipriflavone with a frequency of adverse reactions equal to that observed during administration of a placebo. Despite its structural similarity with some naturally occurring phytoestrogens, ipriflavone has been shown to be devoid of any estrogenic activity in animals and in humans and does not appear to modify secretion or metabolism of endogenous estrogens. See Valente M, Bufalino L, Castiglione G N, et al., Effects of 1-year treatment with ipriflavone on bone in postmenopausal women with low bone mass, Calcif Tissue Int 1994; 54:377-380 and Melis G B, Paoletti A M, Cagnacci A, et al., Lack of any estrogenic effect of ipriflavone in postmenopausal women, J Endocrinol Invest 1992; 15:755-61.
A preliminary cross over (600/1200 mg ipriflavone vs. 1200/600 mg ipriflavone) 30 day study of patients with Paget's disease indicated that ipriflavone supplementation prevented the loss of bone through the inhibition of bone resorption. See Agnusdei D, Camporeale A, Gonnelli S, et al., Short-term treatment of Paget's disease of bone with ipriflavone, Bone Miner. 1992; 19: (Suppl) S35-S42. Following the 1200/600 mg ipriflavone sequence, biochemical measures of bone resorption were affected significantly. Serum alkaline phosphatase (ALP) decreased 33% (P<0.01) and hydroxy proline/creatinine (HOP/Cr) decreased 24.1% (P<0.05). Bone pain was significantly decreased in patients during the 1200/600 mg sequence of ipriflavone. The analgesic effect was rapid and independent of ipriflavone action or bone turnover. The pain relief mechanism is unknown at this time. Id.
A sub-optimal vitamin D status diminishes the production of 1,25-dihydroxyvitamin D (1,25-(OH)2D), which is required for calcium to be actively absorbed in the intestine as well as the homeostatic treatment of calcium by the kidney. See Fraser D R., Vitamin D, The Lancet 1995; 345:104-107. The inadequate absorption will lead to secondary hyperparathyroidism resulting in increased bone resorption and cortical bone loss. Vitamin D status has been correlated with bone mineral density (BMD) of the proximal femur and vertebrae. Supplementation with 1 cc vitamin D increases serum 1,25-(OH)2D levels, increases intestinal calcium absorption, and decreases the secretion of parathyroid hormone (PTH). One study found that elderly women receiving 400 IU 1α vitamin D for one year significantly increased serum 25-hydroxyvitamin D and 1,25-dehydroxyvitamin D, increased BMD at the femoral neck, and significantly decreased PTH. See Ooms M E, Roos J C, Bezemer P D, Van der Vijgh W J, Bouter, L M, Lips P., Prevention of bone loss by 1α vitamin D supplementation in elderly women: a randomized double-blind trial, Journal of Clinical Endocrinology and Metabolism 1995; 80(4):1052-1058. Another short study concluded that IP inhibited bone resorption without affecting bone formation in patients with primary hyperparathyroidism. Mazzouli G F, Romagnoli E, Camevali V, Scarda A, Scamecchia M, Pacitti M T, Rosso R, Minisola V., Effects of ipriflavone on bone modeling in primary hyperparathyroidism, Bone Miner. 1992; 19:S27-S33. The women were supplemented with 1200 mg ipriflavone daily divided in three doses.
Adequate calcium ingestion and absorption is crucial for the maintenance of bone mass. Research indicates that the presence of other food components with elemental calcium greatly increases absorption. Ossein-mineral-compound prepared from calf bone powder has been shown to increase calcium absorption (as compared to synthetic microcrystalline hydroxyapatite) and contains proteins that are mitogenic for bone cells in vitro. See Stepan J J, Mohan S, Jennings J C, et al., Quantitation of growth factors in ossein-mineral-compound, Life Sciences 1991; 49:79-84. Microcrystalline hydroxyapatite from raw whole bone also contains the minerals phosphorus, magnesium, fluoride, zinc, silicon, manganese, copper, and other trace minerals that are physiologically involved in bone formation and metabolism. Trace minerals have catalytic functions (important as cofactors for the proper functioning of specific enzymes) in organic bone matrix that are crucial for the normal development and maintenance of skeletal tissue. See Strause et al., The role of trace elements in bone metabolism, Nutritional Aspects of Osteoporosis, New York: Raven Press; 1991(Strause, 1991). When calcium carbonate and microcrystalline hydroxyapatite were compared for effectiveness in preventing further bone loss in postmenopausal osteoporosis, the calcium carbonate reduced the rate of bone loss by about half, while the microcrystalline hydroxyapatite was shown to nearly halt it. See Seelig M S, Prophylactic treatment of osteoporosis with estrogen and calcium increases need for magnesium, J Am Coll Nutr 1989; 8:457A. Another study of osteoporotic postmenopausal women, with the complication of primary biliary cirrhosis, showed that MCHC supplementation not only helped reduce bone loss but it actually helped increase cortical bone thickness by 6.1%. Abbott L G, Rude R K, Clinical manifestations of magnesium deficiency, Miner Electrolyte Metab 1993; 19:314-322. While prior art formulas as dietary supplements containing calcium or 1α vitamin D or ipriflavone are known and are generally suitable for their limited purposes, they possess certain inherent deficiencies that detract from their overall utility in providing maximal protection against bone loss and maximal increases in bone mass. For example, a dietary supplement containing calcium and 1α vitamin D will increase absorption and utilization of calcium within the body; such a supplement does not offer the benefits of decreased bone resorption that will occur with ipriflavone in accordance with the present invention. Furthermore, a dietary supplement containing ipriflavone alone will not offer the benefits of increases in dietary calcium, other minerals, and vitamins important for bone health. Prior art formulas fail to provide all the components necessary to provide maximal availability of, absorption of, and utilization of, vitamins and minerals essential to optimal bone health in addition to components that decrease bone resorption and increase bone density through increased retention of minerals within the bone.
In view of the foregoing, it will be appreciated that a composition for maximally improving and maintaining bone mass density by providing highly bioavailable calcium, organic bone matrix shown to contain proteins that are mitogenic for bone cells in vitro, a full complement of minerals in the same physiological proportions found in healthy bone to include phosphorus, magnesium, fluoride, zinc, silicon, manganese, and other trace minerals, 1α vitamin D, in addition to components shown to inhibit bone resorption and stimulate bone formation would significantly advance the art.